title: Self-assembled prodrugs: an enzymatically triggered drug-delivery platform.
abstract: Enzyme catalysis as a tool to disassemble supramolecular hydrogels to control the release of encapsulated drugs provides an opportunity to design a wide range of enzyme-specific low-molecular-weight hydrogelators. In this proof-of-concept work, we report the synthesis of low-molecular-weight amphiphilic prodrugs as hydrogelators from a well-known drug acetaminophen (which belongs to a class of drugs called analgesics (pain relievers) and antipyretics (fever reducers)). We have shown the ability of prodrugs to self-assemble to form hydrogels that could subsequently encapsulate a second drug such as curcumin, which is a known chemopreventive and anti-inflammatory hydrophobic drug. Upon enzyme-triggered degradation, the hydrogel released single or multiple drugs at physiologically simulated conditions in vitro. Given that the degradation products consist of the drug and a fatty acid, this approach has an advantage over polymer-based prodrugs that generate polymer fragments with heterogeneous chain lengths upon degradation that may present complex toxicity profiles. Additionally, drug-release occurred without burst release. Spectrophotometric experiments supported the drug-release, and the rate was controlled by modulation of temperature and enzyme concentration. Mesenchymal stem cells treated with prodrugs retained their stem cell properties including the capacity of multi-lineage differentiation, and maintained their adhesive and proliferation capacities with high viability. The present biomaterials could have broad applications as drug-delivery vehicles and cell invasive matrices.
authors.affiliation: Harvard-MIT Division of Health Science and Technology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 65 Landsdowne Street, PRB 313 Cambridge, MA 02139, USA.
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Vemula
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Cruikshank
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Karp
authors.forename: George
authors.initials: G
authors.lastname: John
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology; D016503:Drug Delivery Systems; D006801:Humans; D020100:Hydrogels / Q000737:chemistry; D008049:Lipase / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects; D008855:Microscopy, Electron, Scanning; D008958:Models, Molecular; D010641:Phenotype; D011355:Prodrugs / Q000494:pharmacology*
chemical_list: D020100:Hydrogels; D011355:Prodrugs; D000082:Acetaminophen; D008049:Lipase